[reaction: see text] The first total synthesis of (+/-)-jamtine (4), a tetrahydroisoquinoline alkaloid reputed for its therapeutic properties, is described. The key step involves a tandem thionium/N-acyliminium ion cyclization from enamido sulfoxide 13. The cascade process takes place with high diastereoselectivity and in excellent yield.
The α-thiocarbocation generated from the Pummerer reaction of
N-methyl-N-phenyl-2-[2-(toluene-4-sulfinyl)phenyl]acetamide undergoes Friedel−Crafts reaction at the
γ-carbon with the tethered
aromatic ring. Reductive removal of the phenylthio group from the
resulting product using Raney
nickel occurs in high yield, and the overall reaction represents a new
method for the synthesis of
a variety of 3-phenyl-substituted oxindoles. Treatment of the
related N-benzyl-N-alkyl amido
sulfoxide system with trifluoroacetic anhydride affords
tetrahydroisoquinolone derivatives. The
product distribution encountered coincides with the rotamer population
of the starting amide. When
the N-benzyl-N-methyl amide is used, only the
normal Pummerer product is formed. In this case,
the thionium ion is generated in the wrong conformation for
π-cyclization to occur. The
corresponding N-tert-butyl amido system, however,
exists in a geometric orientation which places
the benzylic group in the crucial conformation necessary for
π-cyclization, and consequently, the
reaction proceeds smoothly. Related cyclization reactions occur in
good yield with the corresponding
furanyl and cyclohexenyl N-tert-butyl amido
sulfoxides. The additive Pummerer reaction of
3-phenylsulfinyl-N-benzyl-N-tert-butylacrylamide
gave products derived from both 5- and 6-exo
trig
cyclizations. Intramolecular electrophilic aromatic substitution
via six-membered ring closure
ultimately afforded a dihydropyridone. The competitive process
involving ipso attack of the aromatic
ring on the thionium ion generates a spiro cyclohexadienyl cation that
undergoes fragmentation of
the adjacent σ-bond. The resulting acyl iminium ion is converted
to N-tert-butyl-2-phenyl-3-phenylsulfinylacrylamide upon aqueous workup. Only cyclizations
leading to five-membered rings
occur with the corresponding indolyl and alkenyl
N-tert-butyl amido sulfoxides.
Albert Padwa* and Alex G. Waterson. Studies Dealing with Thionim Ion Promoted Mannich Cyclization Reactions. Page 238. The transformation of structures 29/30 to 31/32 in Scheme 9 was incorrectly drawn. This scheme should be modified as indicated below. We thank Professor Stephen Martin, University of Texas, for pointing this out to us.
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